ABSTRACT Sleep disturbances are increasingly associated with impaired glucose metabolism, poor cognition, and Alzheimer's disease. Importantly, sleep deprivation is a modifiable risk factor, and elucidating the mechanisms involved may lead to novel, practical approaches to relieve the burden of these conditions on society and our healthcare system. In rodents, prolonged sleep deprivation (SD) leads to progressive metabolic derangements, loss of wake-active neurons, and eventually death. We have found that endoplasmic reticulum (ER) stress in the pancreas (including ? cells) is an early event in this process; even acute SD induces the unfolded protein response (UPR) in bulk pancreas and in ? cells, but not in other peripheral tissues. In the short term, the UPR is an adaptive response that can increase protein-folding capacity and restore homeostasis in cells containing damaged or misfolded proteins by upregulating chaperones such as BiP. However, the failure to resolve misfolding leads to the induction of a pro-apoptotic cascade. ER stress during chronic SD suggests an inability of pancreatic cells to keep up with protein folding demands, resulting in impaired function, and eventually loss of key pancreatic cell types. Loss of ? cells would promote the development of diabetes, whereas damage to the exocrine pancreas could impair nutrient absorption and/or affect the contribution of the gut microbiome. We recently showed that aged mice, which have pre-existing ER stress in the pancreas, are particularly vulnerable to loss/dysfunction of ? cells during eight days of sleep restriction. Given that diabetes is independently associated with the development and progression of Alzheimer's disease, we propose that pancreatic dysfunction including the consequent loss of glucose homeostasis is a mechanism that connects sleep loss to brain aging and neurodegeneration. We will test the following hypotheses: 1) Sleep loss-induced pancreatic ER stress alters endocrine and exocrine functions, and drives glucose dysregulation 2) Pancreatic ER stress is sufficient to augment neuronal injury and accelerate the temporal progression of Alzheimer's disease independently from sleep loss and 3) Alleviating ER stress and restoring protein folding homeostasis in the pancreas can prevent the detrimental effects of sleep loss on Alzheimer's disease progression. Collectively, these studies will critically test the role of pancreatic ER stress in the effects of chronic sleep loss on neuronal health and the temporal progression of Alzheimer's disease. This work has the potential to unveil new therapeutic avenues to prevent brain injury in aging and Alzheimer's disease.